Sequence and functional differences in the ATPase domains of CHD3 and SNF2H promise potential for selective regulability and drugability

Autor:	Leonhard Heizinger, Andreas Fuchs, Stefan Dove, Regina Groebner-Ferreira, Helen Hoffmeister, Laura Strobl, Elizabeth A. Komives, Julian Nazet, Gernot Längst, Rainer Merkl
Rok vydání:	2021
Předmět:	0301 basic medicine Chromosomal Proteins Non-Histone ATPase Chromosomal translocation Binding Competitive Biochemistry Substrate Specificity 03 medical and health sciences Adenosine Triphosphate 0302 clinical medicine Non-competitive inhibition Protein Domains ATP hydrolysis Humans 570 Biowissenschaften Biologie Nucleosome Amino Acid Sequence Molecular Biology Adenosine Triphosphatases chemistry.chemical_classification Sequence Homology Amino Acid biology Hydrolysis DNA Helicases Cell Biology Chromatin Assembly and Disassembly Affinities Chromatin Nucleosomes Cell biology Adenosine Diphosphate 030104 developmental biology Enzyme chemistry 030220 oncology & carcinogenesis Mutation biology.protein ddc:570 ADP chromatin competitive inhibitor remodeling enzyme Mi-2 Nucleosome Remodeling and Deacetylase Complex Protein Binding
Zdroj:	The FEBS Journal. 288:4000-4023
ISSN:	1742-4658 1742-464X
DOI:	10.1111/febs.15699
Popis:	Chromatin remodelers use the energy of ATP hydrolysis to regulate chromatin dynamics. Their impact for development and disease requires strict enzymatic control. Here, we address the differential regulability of the ATPase domain of hSNF2H and hCHD3, exhibiting similar substrate affinities and enzymatic activities. Both enzymes are comparably strongly inhibited in their ATP hydrolysis activity by the competitive ATPase inhibitor ADP. However, the nucleosome remodeling activity of SNF2H is more strongly affected than that of CHD3. Beside ADP, also IP6 inhibits the nucleosome translocation of both enzymes to varying degrees, following a competitive inhibition mode at CHD3, but not at SNF2H. Our observations are further substantiated by mutating conserved Q- and K-residues of ATPase domain motifs. The variants still bind both substrates and exhibit a wild-type similar, basal ATP hydrolysis. Apart from three CHD3 variants, none of the variants can translocate nucleosomes, suggesting for the first time that the basal ATPase activity of the CHD3 is sufficient for nucleosome remodeling. Together with the ADP data our results propose a more efficient coupling of ATP hydrolysis and remodeling in CHD3. This aspect correlates with findings that CHD3 nucleosome translocation is visible at much lower ATP concentrations than SNF2H. We propose sequence differences between the ATPase domains of both enzymes as an explanation for the functional differences and suggest that aa interactions, including the conserved Q- and K-residues distinctly regulate ATPase-dependent functions of both proteins. Our data emphasize the benefits of remodeler ATPase domains for selective drugability and/or regulability of chromatin dynamics.
Databáze:	OpenAIRE
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